Dapagliflozin

Catalog No.S1548

Dapagliflozin is a potent and selective hSGLT2 inhibitor with EC50 of 1.1 nM, exhibiting 1200-fold selectivity over hSGLT1. Phase 4.

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Dapagliflozin Chemical Structure

Dapagliflozin Chemical Structure
Molecular Weight: 408.87

Validation & Quality Control

Quality Control & MSDS

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Product Information

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Product Description

Biological Activity

Description Dapagliflozin is a potent and selective hSGLT2 inhibitor with EC50 of 1.1 nM, exhibiting 1200-fold selectivity over hSGLT1. Phase 4.
Targets hSGLT2 [1]
IC50 1.1 nM(EC50)
In vitro Dapagliflozin is not sensitive to hSGLT1 with a 1200-fold IC50. [1] Dapagliflozin is 32-fold more potent than phlorizin against hSGLT2 but 4-fold less than phlorizin against hSGLT1. Dapagliflozin is highly selective versus GLUT transporters and displays 8–9% inhibition in protein-free buffer at 20 μM and virtually no inhibition in the presence of 4% bovine serum albumin. [2] Dapagliflozin has good permeability across Caco-2 cell membranes and is a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin is stable in rat, dog, monkey, and human serum at 10 μM. Dapagliflozin shows no inhibitory responses or induction to human P450 enzymes. The in vitro metabolic pathways Dapagliflozin are glucuronidation, hydroxylation, and O-deethylation. [3]
In vivo Dapagliflozin reduces blood glucose levels by 55% after 0.1 mg/kg oral dose in hyperglycemic streptozotocin (STZ) rats, which is in part to the metabolic stability conferred by the C-glucoside linkage. Dapagliflozin displays a favorable absorption, distribution, metabolism, and excretion (ADME) profile and is orally bioavailable. [1] Dapagliflozin (1 mg/kg) causes significant dose-dependent glucosuria and increase in urine volume in normal rats over 24 hours post-dose. Dapagliflozin induces increase in urine glucose and urine volume excretion at 6 hours post-dose in Zucker diabetic fatty (ZDF) rats. Dapagliflozin lowers fasting and fed glucose levels in ZDF rats even by 2 weeks of treatment, without any marker of renal or liver toxicity. [2] Dapagliflozin significantly reduces the development of hyperglycaemia, with lowered blood glucose. Dapagliflozin could improve the insulin sensitivity, reduce β-cell mass and the development of impaired pancreatic function. [4]
Features More potent stimulator of glucosuria than other SGLT2 inhibitors.

Protocol(Only for Reference)

Kinase Assay: [1]

SGLT Binding Assays Chinese hamster ovary (CHO) cells stably expressing human SGLT2 (hSGLT2) and human SGLT1 (\hSGLT1) are utilized for the development of transport assays using the selective SGLT substrate α-methyl-D-glucopyranoside (AMG). Dapagliflozin is assayed for the ability to inhibit [14C]AMG uptake in a protein- free buffer over a 2 hours incubation period. The response curve is fitted to an empirical four-parameter model to determine the inhibitor concentration at half maximal response, reported as EC50. Protein-free buffer is used to simulate the low-protein conditions of the glomerular filtrate, which bathes the SGLT targets on the lumenal surface of the proximal tubule in the kidney.

Animal Study: [1]

Animal Models Normal Sprague Dawley rats or streptozotocin induced male Sprague Dawley rats
Formulation 5% mpyrol, 20% PEG400, and 20 mM sodium diphosphate
Dosages 0.01-10 mg/kg (1 mL/kg) followed by a 50% glucose solution (2 g/kg)
Administration Dosed orally
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Meng W, et al. J Med Chem, 2008, 51(5), 1145-1149.

[2] Han S, et al. Diabetes, 2008, 57(6), 1723-1729.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-11-22)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02279407 Not yet recruiting Type 2 Diabetes and Concomitant Fatty Liver Disease (Non-alcoholic Origin) AstraZeneca|Uppsala Clinical Research, Uppsala, Sweden January 2015 Phase 2
NCT02235298 Not yet recruiting Type 2 Diabetes University of Miami January 2015 Phase 4
NCT02284893 Not yet recruiting Type 2 Diabetes Bristol-Myers Squibb|AstraZeneca December 2014 Phase 3
NCT02268214 Not yet recruiting Type 1 Diabetes Mellitus Bristol-Myers Squibb|AstraZeneca November 2014 Phase 3
NCT02253121 Not yet recruiting Hyperglycemia Steroid-induced Slotervaart Hospital|AstraZeneca|Isala|Spaarne Ziekenhuis November 2014 Phase 4

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Chemical Information

Download Dapagliflozin SDF
Molecular Weight (MW) 408.87
Formula

C21H25ClO6

CAS No. 461432-26-8
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms BMS-512148
Solubility (25°C) * In vitro DMSO 82 mg/mL (200.55 mM)
Water <1 mg/mL (<1 mM)
Ethanol 17 mg/mL (41.57 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol

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